1. Field of the Invention
This invention relates to an improved process, suitable for operation on a commercial scale, for the preparation of cationic rhodium complexes of phosphorus-containing chiral ligands. In particular it relates to the preparation of rhodium complexes used as catalysts for asymmetric synthesis, in particular asymmetric hydrogenation.
2. Description of the Prior Art
The efficient production of chiral single enantiomer compounds is one of the most important challenges in modem fine chemical and pharmaceutical manufacturing. The asymmetric hydrogenation of substituted olefins by transition metal complexes modified with chiral phosphorus ligands is an exceptionally powerful method of introducing chirality in to a molecule. This is achieved by preferential binding to one face of the olefin by the transition metal/phosphorus ligand complex and subsequent hydrogenation gives rise to a product enriched in one stereoisomer. Asymmetric hydrogenation is particularly suitable to large-scale hydrogenation due to a variety of factors: use of sub-stoichiometric amounts of catalyst, the clean nature of the reaction and the availability of large-scale equipment. Many classes of phosphorus ligands and transition metal complexes have been developed for asymmetric olefin hydrogenation. Amongst the most effective catalysts are cationic rhodium chiral phosphorus ligand complexes. Their particular success is due to their high catalyst activity, productivity and enantioselectivity.
Fine chemicals and pharmaceutical intermediates hydrogenated by cationic rhodium chiral phosphorus ligand complexes are often complex multifunctional molecules and this complexity is frequently reflected in the requisite chiral phosphorus ligands which are similarly complex in structure and often made via multistep syntheses. As a consequence many of the most effective chiral phosphorus ligands are exceptionally difficult and costly to synthesise and the efficient formation of cationic rhodium phosphine complexes is a critical aspect of the economic viability of an asymmetric hydrogenation catalyst or its subsequent application in hydrogenation processes.
In principle cationic rhodium chiral phosphorus ligand complexes can be generated in two ways: 1) in-situ by mixing the chiral ligand and a suitable metal precursor or by 2) using a preformed complex. Using an in-situ formed catalyst has several distinct disadvantages: 1) many ligands are very oxygen sensitive and can be readily oxidised by poor handling; 2) in-situ catalyst formation introduces an extra process step; 3) in-situ generation of a catalyst can also give rise inconsistent results; 4) incorrect metal/ligand stoichiometry can adversely effect catalyst activity and selectivity. Such factors may limit applicability in pharmaceutical manufacturing from a regulatory as well as a technical viewpoint. However, use of a preformed complex can overcome these difficulties: 1) complexation of a sensitive ligand by a metal centre can stabilise the ligand; 2) preformed catalysts can be easily handled and introduced into a process avoiding an additional step and 3) a preformed catalyst will be a well defined and characterised species which gives more consistent results.
As asymmetric hydrogenation catalysts are most often used in the synthesis of high value active pharmaceutical ingredients, pharmaceutical intermediates and other fine chemicals it is of the utmost importance to guarantee the integrity of the catalyst and this can be readily achieved by use of preformed species. However, it is challenging to establish reliable and economic processes to prepare and isolate such cationic rhodium complexes in a form suitable for storage. This point is highlighted by the inability, to date, to form a crystalline cationic rhodium catalyst of adequate storage stability with the commercially available chiral ligand RoPHOS. Isolated solid cationic rhodium catalyst produced from RoPHOS undergoes spontaneous decomposition leading to loss of valuable catalyst and ligand (Conference Proceedings, Chiral Europe 2003, M. Thommen, Solvias A G).
The numerous chiral phosphorus ligand complexes described in the literature have given rise to a variety of synthetic routes to their corresponding cationic rhodium catalysts. The most common method for the preparation of cationic rhodium phosphorus complexes is the treatment of [(1,5-cyclooctadiene)2Rh][X], where X is an anion and typically [BF4]−, [PF6]−, [SbF6]−, [ClO4]−, or [OSO2CF3]− with a requisite chiral phosphorus ligand. For representative examples see: J. Am. Chem. Soc. 1971, 73, 2397; Helv. Chem. Acta. 1991, 74, 370; Organometallics 2003, 93, 1356; Organometallics 2002, 21, 461 1; J. Am. Chem. Soc. 1993, 115, 10125. Where low polarity solvents are used to aid product recovery, inclusion of the metal-precursor in the product is a hazard due to the relative insolubility of [(1,5-cyclooctadiene)2Rh][X] in low polarity solvents. Contamination of the chiral cationic rhodium catalyst with the achiral metal-precursor can reduce the overall stereoselectivity of the asymmetric hydrogenation. This problem can be overcome by using an excess of ligand, however, where expensive ligands are employed this option is undesirable. Moreover, further reaction of the preformed complex and excess ligand are a possibility giving rise to species less selective than the desired catalyst. Use of [(1,5-cyclooctadiene)2Rh][X] in more polar solvents such as tetrahydrofuran often requires evaporation, trituration with an anti-solvent and crystallisation steps to obtain pure product.
In an alternative process, the chlorido precursor [(1,5-cyclooctadiene)RhCl]2 can be treated with salts such as AgBF4, AgPF6, AgClO4, AgSbF6, NH4PF6, NaBF4, NaSbF6 and NaClO4 to abstract the chloride and treatment with a requisite phosphorus ligand can give rise to a cationic rhodium catalyst. For representative examples see: J. Organometall. Chem. 1999, 577, 346; J: Organometall. Chem. 1983, 251, 79, Helv. Chim. Acta. 1988, 71, 897; Bull. Chem. Soc. Jpn. 1984, 57, 2171; Inorg. Chem. 1980, 19, 577; J. Organometall. Chem. 1982, 239, 1. This route is disadvantageous for large scale applications as silver salts such as AgBF4 and AgSbF6 are expensive reagents. Furthermore, the AgCl generated must be removed by filtration before using the catalyst in subsequent reactions. Where salts such as NaBF4 or NH4PF6 are used the chloride salts generated must be removed via an aqueous wash, thus adding additional separation and drying steps to remove salts and water. Also labile ligands such as phosphoramidites, phosphonites and phosphates are unsuitable for this method due to the reactivity towards moisture. Moreover, contamination of the cationic catalyst with chloride can be particularly detrimental to catalyst performance as highlighted by Cobley et al in Organic Process Research & Development 2003, 7, 407.
In another process where [(1,5-cyclooctadiene)Rh(acetylacetonate)] is treated with aqueous HClO4, a cationic rhodium catalyst can be generated by addition of an appropriate phosphorus ligand, Inorg. Chem. 1981, 20, 3616. Yields can be variable using this method and also close examination of the reaction liquors by 31P-NMR reveals the presence of a variety species other than product thus limiting the maximum yield of the reaction. Use of the aqueous acids such HClO4 limits the scope of chiral phosphorus ligands applicable in this method. Common chiral phosphorus ligands such as phosphites, phosphonites and phosphoramidites cannot be used with aqueous acids as the reaction conditions applied lead to decomposition of the ligand.
In a related method Schmutzler (Z. Anorg. Allg. Chem. 2002, 628, 545 and Z. Anorg. Allg. Chem. 2002, 628, 779) has shown direct reaction of [(1,5-cyclooctadiene)Rh(acetylacetonate)] with calixarene derived phosphites and biurets at −78° C. followed by subsequent reaction with ethereal HBF4 can give rise to cationic rhodium phosphorus complexes, albeit in reduced yield and as an air- and moisture-sensitive form.
Another method of producing cationic rhodium phosphorus complexes is the reaction of [(norbomadiene)Rh(acetylacetonate)] with Ph3CBF4 and a suitable chiral phosphorus ligand, J. Am. Chem. Soc. 1983, 105, 7288. The applicability of this method in the industrial case is low due to the prohibitive cost of the reagent Ph3CBF4, furthermore the reaction required a reaction temperature of −78° C. and the product was only obtained after concentration, trituration and recrystallisation.
A common feature of the catalyst preparations described is the need for further manipulation of the crude reaction mixtures to isolate the catalyst. Most catalyst preparations result in a homogeneous solution whereby the catalyst must be precipitated from the reaction mixture by addition of an anti-solvent. Addition of anti-solvents commonly gives rise to rapid precipitation of microcrystalline or amorphous material with large surface areas. This is particularly disadvantageous as microcrystalline and amorphous materials are thermodynamically less stable than crystalline materials and can result in poor storability, poor handling ability and accelerated decomposition of the catalyst. In the industrial case, where catalysts are often purchased or prepared far in advance of their use, poor stability of the catalyst can have deleterious effects on the outcome of manufacturing campaigns and have significant financial implications due to loss of catalysts and compromised selectivities and yields. Often there is a need to recrystallise catalysts isolated via precipitation as the material is microcrystalline and of insufficient purity. This adds a further step and results in a reduced overall yield.
A manufacturing process for cationic rhodium catalysts that consistently produces high purity, crystalline material with a large range of phosphorus-containing ligands would be particularly advantageous. In contrast to the prior art the process of the present invention meets these requirements for industrial viability.